The effects of gp120-mediated signal transduction in viral replication and immune dysfunction that leads to HIV pathogenesis is the major focus of this project. In the past we demonstrated the capacity of gp120 to engage the gut homing receptor, integrin alpha4beta7. The gut is the principal site of viral replication and CD4+ T cell depletion during the acute stage of infection. Based on this notion, we explored the role of alpha4beta7 expressing CD4+ T cells in HIV transmission. We tested this hypothesis in a NHP model of HIV/SIV infection, and determined that an antibody specific for alpha4beta7 prevented transmission in a rhesus macaque model of mucosal transmission. We subsequently tested the impact of this alpha4beta7 antagonist in an in vivo NHP study in the context of anti-retroviral (ART) treatment. SIV-infected monkeys were treated with ART initiated at 5 weeks post infection followed by infusions of the primatized antibody alpha4beta7 integrin administered every 3 weeks until week 32. These animals subsequently maintained low to undetectable viral loads and normal CD4+ T cell counts in plasma and gastrointestinal tissues for more than 9 months, even after all treatment was withdrawn. This combination therapy allowed macaques to effectively control viremia and reconstitute their immune systems without the need for further therapy. Of note, we have employed in our NHP studies a primatized version of vedolizumab, an FDA approved drug employed for the treatment of inflammatory bowel diseases (IBDs). The combination of ART and vedolizumab is now being tested in a human clinical trial.